Tumour therapy is mostly implemented through the use of substances targeted at destroying cancer cells. This can be achieved with cytotoxic substances, which have to penetrate into the tumour cells in order to exert their full effect, or by means of treatment of the tumour cells with radiation of sufficient energy to kill the cells. In both cases there is the problem of delivering the substance in as selective a manner as possible to the target cells, so as to avoid possible damage to the surrounding healthy cells. In the case of radiopharmaceuticals, i.e. substances carrying radioactive portions, the problem of selectively delivering the active part (that is, the radioactive portion) to the tumour target, avoiding as far as possible diffusion of the radionuclide in the body or interaction with healthy cells surrounding the tumour, is perceived as being particularly important.
For a discussion of all the issues involved and the solutions proposed to date, the reader is referred to U.S. Pat. Nos. 5,283,342, 5,608,060 and 5,955,605, assigned to Neorex, and based on a patent application filed on Jun. 9, 1992. These patents are specifically incorporated herein for reference purposes.
In these documents, the problem, amongst others, of the resistance of the molecule carrying the radionuclide to the metabolic attacks of the body is discussed. Specifically, the case accorded most attention is the molecule of biotin, which is one of the first choices for delivering the radionuclide to the tumour cells, thanks to its well-known interaction with avidins. Biotin, as we know from consolidated practice, is bound to the radionuclide-chelating portion, e.g. a molecule of DOTA, via a linker. In fact, the Neorex patents pose the problem of the resistance of the complex consisting of the biotin molecule, as connected to the radionuclide via the linker, to biotinidases, enzymes that break the peptide bond present in the complex. This bond stems from the union of the chelating agent and biotin.
Among its much desired characteristics, the molecule must be eliminated from the body rapidly and efficiently and must be sufficiently small (m.w.<1000) to allow easy distribution into the extracellular fluid where it will bind with the tumour. In addition, it must show proven stability in vivo with only minimal uptake by non-tumour cells and rapid (renal) clearance and must not be metabolised.
To these characteristics one should add the need for a certain amount of stability between the biotin part and the chelating portion of the molecule.
In fact, the chelating portion must not be released in vivo, freeing parts of the molecule, which are potentially dangerous for the body. Experts in the field are clearly familiar with the problem of the release of radionuclide by the chelating portion, including metal ions which are entirely foreign to the body, which may be endowed with radioactivity of various types and even high-energy radiation, which is therefore highly damaging.